Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study

M1 muscarinic acetylcholine receptor (M1-AChR), a member of the G protein-coupled receptors (GPCR) family, plays a crucial role in learning and memory, making it an important drug target for Alzheimer's disease (AD) and schizophrenia. M1-AChR activation and deactivation have shown modifying effects in AD and PD preclinical models, respectively. However, understanding the pharmacology associated with M1-AChR activation or deactivation is complex, because of the low selectivity among muscarinic subtypes, hampering their therapeutic applications. In this regard, we constructed two quantitative structure–activity relationship (QSAR) models, one for M1-AChR agonists (total and partial), and the other for the antagonists. The binding mode of 59 structurally different compounds, including agonists and antagonists with experimental binding affinity values (pKi), were analyzed employing computational molecular docking over different structures of M1-AChR. Furthermore, we considered the interaction energy (Einter), the number of rotatable bonds (NRB), and lipophilicity (ilogP) for the construction of the QSAR model for agonists (R2 = 89.64, QLMO2 = 78, and Qext2 = 79.1). For the QSAR model of antagonists (R2 = 88.44, QLMO2 = 82, and Qext2 = 78.1) we considered the Einter, the fraction of sp3 carbons fCsp3, and lipophilicity (MlogP). Our results suggest that the ligand volume is a determinant to establish its biological activity (agonist or antagonist), causing changes in binding energy, and determining the affinity for M1-AChR.

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Molecule Hydrophobic contact
Carbon Hydrogen Bond Electrostatic Distance (Å) The crystal structure of the M1 receptor with 77-LH-28-1 bound (PDB code: 6ZFZJ) was used as a template to assess the different M1R-ligand interactions.

Molecule Hydrophobic contact
Carbon Hydrogen Bond Electrostatic Distance (Å) The crystal structure of the M1 receptor with atropine bound (PDB code: 6WJC) was used as a template to assess the different M1R-ligand interactions.

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Figure-S3Crystal structure of the M1AChR-iperoxo complex (PDB:6OIJ) with the overlapping ligand pose obtained from docking (RMSD=0.82Å).The conformation obtained from the docking calculation is green, and the crystal conformation is cyan.

Figure
Figure-S4 Crystal structure of the M1R-77-LH-28-1 complex (PDB:6ZFZ) with the overlapping ligand pose obtained from docking (RMSD=0.85Å).The conformation obtained from the docking calculation is green, and the crystal conformation is cyan.

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Figure-S5 Crystal structure of the M1R-atropine complex (PDB:6WJC) with the overlapping ligand pose obtained from docking (RMSD=1.2Å).The conformation obtained from the docking calculation is green, and the crystal conformation is cyan.

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Figure-S6 Crystal structure of the M1R-tiotropium complex (PDB:5CXV)) with the overlapping ligand pose obtained from docking (RMSD=0.29 Å).The conformation obtained from the docking calculation is green, and the crystal conformation is cyan.

BIOVIA Discovery Studio Visualizer analysis. Comparative analysis of the interaction types and amino acids involved at M1AChR.
S8 Data values of agonists of M1-AChR obtained from the QSAR model.Figure-S10.1Thecrystal structure of the M1 receptor with iperoxo bound (PDB code: 6OIJ) was used as a template to assess the different M1R-ligand interactions.
type descriptors using slogp and mr contributions and surface area contributions, moe-type descriptors using partial charges and surface area contributions, moe-type descriptors using estate indices and surface area contributions, moe-type descriptors using surface area contributions and estate indicesChemDes Figure-